Compounds of the general Formula I have been described as effective long lasting cardiac antiarrhythmic agents. ##STR1##
Of particular interest are the compounds of Formula I wherein variable n is zero, compounds generally described as .alpha.-aminoacylanilides. Tocainide, an example of an .alpha.-aminoacylanilide, is a commercially marketed antiarrhythmic agent.
Synthetic preparations of compounds of the Formula I wherein n is zero have been previously described (see for example U.S. Pat. No. 4,218,477).
Of the known synthetic routes the preferred preparation of the .alpha.-aminoacylanilides comprises synthesis of the suitably substituted .alpha.-haloacylanilide followed by reaction of the haloacylanilide and ammonia gas in a suitable organic/aqueous solvent. The reaction of the haloacylanilide typically proceeds in high yield; however, because the terminal nitrogen of the product, .alpha.-aminoacylanilide, is comparable in nucleophilicity to ammonia, a byproduct of the Formula II may form in amounts which are unacceptable for pharmaceutical applications. ##STR2##
Small amounts of byproducts of the Formula II may be removed, or reduced to be within acceptable pharmaceutical limits, by recrystallization of the reaction product or washing the reaction product with a suitable organic solvent. However, this additional step presents added economic costs and the potential utilization of environmentally harmful solvents.
An alternative amination procedure utilizes aqueous ammonia in high dilution without an organic cosolvent. While the amount of the above described byproduct is reduced under this reaction condition, it is still present in such amounts as to require further purification as previously described. This second procedure is also unacceptable because of the enormous size of the vessels which would be required for implementation on a manufacturing scale. Thus, there now exists a need for a simple, economic procedure for preparing .alpha.-aminoacylanilides from .alpha.-haloacylanilides wherein the dimeric byproduct of the reaction is substantially reduced or eliminated.
It is an object of the instant invention to provide an improved process for the preparation .alpha.-aminoacylanilides by amination of the corresponding .alpha.-haloacylanilides with a solution of ammoniun carbamate in aqueous ammonia. It has been surprisingly discovered that under these conditions the unwanted dimer byproduct has been essentially eliminated from the crude reaction product.
The .alpha.-aminoacylanilide compound of Formula I produced by the process of the present invention is useful per se as an antiarrhythmic agent, such as disclosed in U.S. Pat. No. 4,218,477. It is also understood that the compound of Formula I may be further modified and that such modification may lead to other pharmaceutical agents, such as disclosed in U.S. Pat. No. 4,169,106 and PCT application WO 91/12265.